This invention relates to the preparation of substituted chromanol derivatives and to intermediates useful in said preparation. The substituted chromanol derivatives that are prepared in accord with the present invention are disclosed in U.S. patent application Ser. No. 08/295,827, filed Jan. 9, 1995, entitled xe2x80x9cBenzopyran And Related LTB4 Antagonists,xe2x80x9d PCT international application publication number WO 96/11925 (published Apr. 25, 1996), PCT international application publication number WO 96/11920 (published Apr. 25, 1996), PCT international application publication number WO 93/15066 (published Aug. 5, 1993). Each of the foregoing United State and PCT internation patent applications are incorporated herein by reference in their entirety.
The substituted chromanol derivatives that are prepared in accord with the present invention inhibit the action of LTB4, as disclosed in U.S. patent application Ser. No. 08/295,827, referred to above. As LTB4 antagonists, the substituted chromanol derivatives that are prepared according to the present invention are useful in the treatment of LTB4-induced illnesses such as inflammatory disorders including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis, eczema, erythma, pruritis, acne, stroke, graft rejection, autoimmune diseases, and asthma.
The present invention relates to a process of preparing a compound of the formula 
or the enantiomer of said compound, wherein in said compound of formula X the R3-substituted benzoic acid moiety is attached at carbon 6 or 7 of the chroman ring;
R1 is xe2x80x94(CH2)qCHR5R6 wherein q is 0 to 4;
each R2 and R3 is independently selected from the group consisting of H, fluoro, chloro, C1-C6 alkyl, C1-C6 alkoxy, phenylsulfinyl, phenylsulfonyl, and xe2x80x94S(O)n(C1-C6 alkyl) wherein n is 0 to 2, and wherein said alkyl group, the alkyl moiety of said alkoxy and xe2x80x94S(O)n(C1-C6 alkyl) groups, and the phenyl moiety of said phenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1 to 3 fluoro groups;
R5 is H, C1-C6 alkyl, or phenyl substituted by R2;
R6 is H, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C1 aryl, or 5-10 membered heteroaryl, wherein said aryl and heteroaryl groups are optionally substituted by 1 or 2 substituents independently selected from phenyl, R2, and phenyl substituted by 1 or 2 R2;
which comprises treating a compound of the formula 
or the enantiomer of said compound of formula IX in the preparation of the enantiomer of said compound of formula X, wherein R1, R2, and R3 are as defined above, R4 is C1-C6 alkyl, and the benzoate moiety is attached to position 6 or 7 of the chroman ring, with a base.
In said process of preparing the compound of formula X, the compound of formula IX is preferably treated with an aqueous hydroxide base, R1 is preferably benzyl, 4-fluorobenzyl, 4-phenylbenzyl, 4-(4-fluorophenyl)benzyl, or phenethyl, R2 is preferably hydrogen or fluoro, R3 is preferably fluoro, chloro, or methyl optionally substituted by 1 to 3 fluorines, and R4 is preferably ethyl or 2,2-dimethylpropyl. Most preferably, said compound of formula IX is treated with a base comprising aqueous sodium hydroxide, said compound of formula IX is (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid ethyl ester, and said compound of formula X is (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid.
In a further aspect of the present invention, said compound of formula IX, or the enantiomer of said compound, wherein R1, R2, R3, and R4 are as defined above, is prepared by treating a compound of the formula 
or the enantiomer of said compound of formula VII in the preparation of the enantiomer of the compound of formula IX, wherein R1 and R2 are as defined above and the boronic acid moiety is attached at position 6 or 7 of the chroman ring, with a compound of the formula 
wherein R3 and R4 are as defined above and Z is halo or C1-C4 perfluoroalkylsulfonate, in the presence of a base or fluoride salt and a palladium catalyst.
In said process of making the compound of formula IX, or the enantiomer of said compound, preferred substituents for R1, R2, R3 and R4 are as stated above for said process of making the compound of formula X. In another preferred embodiment, Z is halo, the base or fluoride salt is selected from sodium carbonate, triethylamine, sodium bicarbonate, cesium carbonate, tripotassium phosphate, pottasium fluoride, cesium fluoride, sodium hydroxide, barium hydroxide, and tetrabutylammonium fluoride, the palladium catalyst is selected from tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate, allylpalladium chloride dimer, tris(dibenzylideneacetone)dipalladium(0), and 10% palladium on carbon. Most preferably, the base or fluoride salt is potassium fluoride, the palladium catalyst is 10% palladium on carbon, the compound of formula VII is (3S,4R)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronic acid, and the compound of formula VII is ethyl2-iodo-4-trifluoromethyl-benzoate.
In a further aspect of the invention, the compound of formula VII, or the enantiomer of said compound, wherein R1 and R2 are as defined above, is prepared by treating a compound of the formula 
or the enantiomer of said compound of formula VI in the preparation of the enantiomer of the compound of formula VII, wherein R1 and R2 are as defined above and X is a halide and is attached at position 6 or 7 of the chroman ring, with (1) C1-C4 alkyl lithium, and (2) a borating agent.
In said process of making the compound of formula VII, or the enantiomer of said compound, preferred substituents for R1 and R2 are as stated above for said process of making the compound of formula X. In another preferred embodiment, X is bromo or iodo, and said compound of formula VI is treated with (1) methyl lithium, (2) butyl lithium, and (3) said borating agent which is selected from borane-tetrahydrofuran complex, triisopropyl borate, and trimethyl borate. Most preferably, the compound of formula VI is (3S,4R)-3-benzyl-7-bromo-chroman-4-ol and said borating agent is borane-tetrahydrofuran complex.
In a further aspect of the invention, the compound of formula VI, or the enantiomer of said compound, wherein R1, R2 and X are as defined above, is prepared by treating a compound of the formula 
or the enantiomer of said compound of formula V in the preparation of the enantiomer of the compound of formula VI, wherein R1 , R2 and X are as defined above and X is attached at position 4 or 5 of the phenyl ring, and Y is halo or nitro, with a base, optionally in the presence of added copper salts.
In said process of making the compound of formula VI, or the enantiomer of said compound, preferred substituents for R1, R2 and X are as stated above for said process of making the compound of formula VII. In another preferred embodiment, Y is halo, and said base is potassium tert-butoxide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, cesium carbonate, or sodium hydride. Most preferably, said base is potassium tert-butoxide and the compound of formula V is (1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol.
In a further aspect of the invention, the compound of formula V, or the enantiomer of said compound, wherein R1, R2, X and Y are as defined above, is prepared by treating a compound of the formula 
or the enantiomer of said compound of formula IV in the preparation of the enantiomer of the compound of formula V, wherein R1, R2, X and Y are as defined above and X is attached at position 4 or 5 of the phenyl ring, and Xc is a chiral auxiliary, with a hydride reducing agent.
In said process of making the compound of formula V, or the enantiomer of said compound, preferred substituents for R1, R2, X and Y are as stated above for said process of making the compound of formula VI. In another preferred embodiment, Xc is (R)-4-benzyl-2-oxazolidinone, (S)4-benzyl-2-oxazolidinone, (4R, 5S) -4-methyl-5-phenyl-oxazolidin-2-one, or (4S,5R)-4-methyl-5-phenyl-oxazolidin-2-one, wherein Xc is attached at the nitrogen of the oxazolidin-2-one ring, and said reducing agent is lithium borohydride, lithium aluminum hydride, sodium borohydride, or calcium borohydride. Most preferably, the compound of formula IV is [4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one, 1-methyl -2-pyrrolidinone solvate or [4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one, and said reducing agent is lithium borohydride.
In a further aspect of the invention, the compound of formula IV, or the enantiomer of said compound, wherein R1, R2, X, Xc and Y are as defined above, is prepared by treating a compound of the formula R1xe2x80x94CH2C(O)xe2x80x94Xc, wherein R1 and Xc are as defined above, with (1) a Lewis acid, (2) a base, and (3) a compound of formula 
wherein R2, X and Y are as defined above and X is attached at position 4 or 5 of the phenyl ring.
In said process of making the compound of formula IV, or the enantiomer of said compound, preferred substituents for R1, R2, X, Xc and Y are as stated above for said process of making the compound of formula V. In another preferred embodiment, said Lewis acid is a boron halide or sulfonate, and said base is triethylamine or diisopropylethylamine. Most preferably, said compound of formula R1xe2x80x94CH2C(O)xe2x80x94Xc is (R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one, said compound of formula III is 4-bromo-2-fluoro-benzaldehyde, said Lewis acid is dibutylboron triflate, and said base is triethylamine.
In a further aspect of the invention, the compound of formula IV, or the enantiomer of said compound, wherein R1, R2, X, Xc and Y are as defined above, is prepared by treating a compound of the formula R1xe2x80x94CH2C(O)xe2x80x94Xc, wherein R1 and Xc are as defined above, with (1) a titanium(IV) halide, (2) a base optionally followed by treatment with a donor ligand, and (3) a compound of formula 
wherein R2, X and Y are as defined above and X is attached at position 4 or 5 of the phenyl ring.
In said process of making the compound of formula IV, or the enantiomer of said compound, preferred substituents for R1, R2, X, Xc and Y are as stated above for said process of making the compound of formula V. In another preferred embodiment, said titanium(IV) halide is titanium tetrachloride, and said base is a tertiary amine or tertiary diamine base. In another preferred embodiment, said base is triethylamine or N,N,Nxe2x80x2Nxe2x80x2-tetramethylethylenediamine,and said treatment with said base is followed by treatment with a donor ligand selected from 1-methyl-2-pyrrolidinone, dimethylformamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone, triethylphosphate, and 2,2xe2x80x2-dipyridyl. Most preferably, said compound of formula R1xe2x80x94CH2C(O)xe2x80x94Xc, is (R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one, said compound of formula III is 4-bromo-2-fluoro-benzaldehyde, said base is N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine, and said donor ligand is 1-methyl-2-pyrrolidinone.
In a further aspect of the invention, said compound of formula IX, or the enantiomer of said compound, wherein R1, R2 , R3 and R4 are as defined above, is prepared by coupling a compound of the formula 
or the enantiomer of said compound in the preparation of the enantiomer of the compound of formula IX, wherein R1 and R2 are as defined above and Xxe2x80x2, which is attached at position 6 or 7 of the chroman ring, is halo or C1-C4 perfluoroalkylsulfonate, with a compound of the formula 
wherein R3 and R4 are as defined above, in the presence of a base or fluoride salt and a palladium catalyst.
In the process of preparing the compound of formula IX, or the enantiomer of said compound, as recited directly above, preferred substituents for R1 , R2, R3 and R4 are as stated above for the process of making the compound of formula X. In another preferred embodiment, Xxe2x80x2 is preferably bromo, iodo, or trifluoromethanesulfonate, the palladium catalyst is preferably selected from tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate, allylpalladium chloride dimer, tris(dibenzylideneacetone)dipalladium(0), and 10%palladium on carbon, and the base or fluoride salt is selected from sodium carbonate, triethylamine, sodium bicarbonate, cesium carbonate, tripotassium phosphate, pottasium fluoride, cesium fluoride, sodium hydroxide, barium hydroxide, and tetrabutylammonium fluoride. Most preferably, the compound of formula VI is (3S,4R)-3-benzyl-7-bromo-chroman-4-ol, the compound of formula XIV is 2-(2,2-dimethyl-propoxycarbonyl-5-trifluoromethyl -benzeneboronic acid, the base or fluoride salt is sodium carbonate, and the palladium catalyst is tetrakis(triphenylphosphine)palladium(0).
In a further aspect of the invention, the compound of formula XIV, wherein R3 and R4 are as defined above, is prepared by hydrolyzing a compound of the formula 
wherein R3 and R4 are as define above, the dashed line indicates a bond or no bond between the B and N atoms, n and m are independently 2 to 5, and R8 is H or C1-C6 alkyl. R8 is preferably H and preferred substituents for R3 and R4 are as stated above for said process of making a compound of formula X. Preferably, said hydrolysis is effected with an acid, such as hydrochloric acid, and n and m are each 2. Most preferably, said compound of formula XVI is 2-[1,3,6,2]dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid 2,2-dimethyl-propyl ester.
In a further aspect of the invention, the compound of formula XVI, wherein R3, R4 and R8 are as defined above, is prepared by reacting a compound of formula XIV, wherein R3 and R4 are as defined above, with a compound of formula HO(CH2)mxe2x80x94N(R8)xe2x80x94(CH2)nOH (formula XV), wherein n, m and R8 are as defined above. In said process of preparing the compound of formula XVI, preferred substituents for R3 and R4 are as stated above for said process of preparing a compound of formula X. Most preferably, said compound of formula XIV is 2-(2,2-dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic acid and said compound of formula XV is diethanolamine.
In a further aspect of the invention, the compound of formula XIV, wherein R4 and R3 are as defined above, is prepared by hydrolyzing a compound of the formula 
wherein R3 and R4 are as defined above and R7 is C1-C6 alkyl. Said hydrolysis is preferably effected with an acid, such as hydrochloric acid. Preferred substituents for R3 and R4 are as stated above for said process of making a compound of formula X.
In a further aspect of the invention, the compound of formula XIII, wherein R3, R4 and R7 are as defined above, is prepared by treating a compound of the formula 
wherein R3 and R4 are as defined above, with a metal amide base in the presence of a tri-(C1-C6 alkyl)borate.
In said process of making the compound of formula XIII, preferred substituents for R3 and R4 are as stated above for said process of making the compound of formula X. In another preferred embodiment, said metal amide base is selected from lithium diisopropylamide, lithium diethylamide, lithium 2,2,6,6-tetramethylpiperidine, and bis(2,2,6,6-tetramethylpiperidino)magnesium, and said tri-(C1-C4alkyl)borate is selected from triisopropylborate, triethylborate, and trimethylborate. Most preferably, the compound of formula XII is 4-trifluoromethyl-benzoic acid 2,2-dimethyl-propyl ester, said metal amide base is lithium diisopropylamide, and said tri-(C1-C6 alkyl)borate is triisopropylborate.
In a further aspect of the invention, the compound of formula X, or the enantiomer of said compound, wherein R1, R2, and R3 are as defined above, is reacted with a secondary amine of the formula NHR5R6, wherein R5 and R6 are as defined above, to form an ammonium carboxylate of the formula 
or the enantiomer of said compound of formula XVII,wherein R1, R2, R3, R5 and R6 are as defined above. Preferred substituents for R1, R2, and R3 are as stated above for said process of making a compound of formula X. In said secondary amine, R5 and R6 are each preferably cyclohexyl. Most preferably, said compound of formula XVII is (3S,4R)-dicyclohexylammonium-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl benzoate.
The invention also relates to a process of preparing a compound of the formula 
or the enantiomer of said compound, wherein Rxe2x80x2 and Xc are as defined above for said process of preparing a compound of formula V, and R11 is C1-C9 alkyl, C2-C9 alkenyl or phenyl substituted by Y in the 2 position, X in the 4 or 5 position, and R2 in one of the remaining positions of the phenyl moiety, wherein Y, X and R2 are as defined above for said process of preparing a compound of formula V, by treating a compound of the formula R1xe2x80x94CH2C(O)xe2x80x94Xc, wherein Rxe2x80x2 and Xc are as defined above, with (1) a titanium(IV) halide, (2) a base optionally followed by treatment with a donor ligand, and (3) less than 2 equivalents, preferably about 1 equivalent, of a compound of the formula R11xe2x80x94C(O)H, wherein R11 is as defined above, relative to the amount of said compound of formula R1xe2x80x94CH2C(O)xe2x80x94Xc. Preferred substituents and reagents for said process of preparing said compound of formula XIX, or the enantiomer of said compound, are as stated above for said process of preparing a compound of formula IV using said titanium(IV) halide.
The invention also relates to a compound of the formula 
and to the enantiomer of said compound, wherein R1, R2, X and Y are as stated above for said process of preparing a compound of the formula VI.
In said compound of formula V, and the enantiomer of said compound, preferred substituents for R1, R2, X and Y are as stated above for said process of preparing a compound of the formula VI. Most preferably, said compound of formula V is (1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol.
The invention also relates to a compound of the formula 
and to the enantiomer of said compound, wherein R1 and R2 are as stated above for said compound of formula V and Xxe2x80x2 is halo or C1-C4 perfluoroalkylsulfonate and is attached at position 6 or 7 of the chroman ring.
In said compound of formula VI, and the enantiomer of said compound, preferred substituents for R1 and R2 are as stated above for said compound of formula V, and Xxe2x80x2 is preferably bromo, iodo, or trifluoromethanesulfonate. Most preferably, said compound of the formula VI is (3S,4R)-3-benzyl-7-bromo-chroman-4-ol.
The invention also relates to a compound of the formula 
and to the enantiomer of said compound, wherein R1 and R2 are as stated above for said compound of formula VI.
In said compound of formula VII, and the enantiomer of said compound, preferred substituents for R1 and R2 are as stated above for said compound of formula VI. Most preferably, said compound of the formula VII is (3S,4R)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronic acid.
The invention also relates to a compound of the formula 
and to the enantiomer of said compound, wherein R1, R2, R3 and R4 are as stated above for said process of preparing a compound of the formula X and the benzoate moiety is attached to position 6 or 7 of the chroman ring.
In said compound of formula IX, and the enantiomer of said compound, preferred substituents for R1, R2, R3 and R4 are as stated above for said process of preparing a compound of the formula X. Most preferably, the compound of formula IX is (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoiacidethylester.
The invention also relates to a compound of the formula 
wherein R3, R4 and R7 are as stated above for said process of preparing a compound of the formula XIV using a compound of formula XIII.
In said compound of formula XIII, preferred substituents for R7, R3 and R4 are as stated above for said process of preparing a compound of the formula XIV using a compound of formula XIII.
The invention also relates to a compound of the formula 
wherein R3 and R4 are as stated above for said compound of formula XIII.
In said compound of formula XIV, preferred substituents for R3 and R4 are as stated above for said compound of formula XIII. Most preferably, said compound of the formula XIV is 2-(2,2-dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic acid.
The invention also relates to compounds of the formula 
wherein the dashed line indicates a bond or no bond between the B and N atoms, n and m are independently 2 to 5, R3 and R4 are as defined above for said compound of formula XIV, and R8 is H or C1-C6 alkyl.
In said compound of formula XVI, n and m are each preferably 2, preferred substituents for R3 and R4 are as defined above for said compound of formula XIV, and R8 is preferably H. Most preferably, the compound of formula XVI is 2-[1,3,6,2]dioxazaborocan-2-yl-4-trifluoromethyl-benzoicacid 2,2-dimethyl-propylester.
The invention also relates to an ammonium carboxylate compound of the formula 
and to the enantiomer of said compound, wherein R1, R2, R3, R5 and R6 are as defined above for said process of preparing a compound of the formula X. Preferred substituents for R1, R2, and R3 are as stated above for said process of making a compound of formula X. In the ammonium moiety, R5 and R6 are each preferably cyclohexyl. Most preferably, said compound of formula XVII is (3S,4R)-dicyclohexylammonium-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl benzoate.
The present invention also relates to a compound of the formula 
and to the enantiomer of said compound, wherein R1, R2, X, Y and Xc are as defined above for said process of preparing a compound of formula V. The present invention also relates to solvates of said compound of formula IV and the enantiomer of said compound of formula IV. Preferred solvates of said compound of formula IV, and the enantiomer of said compound, are those formed with a donor ligand selected from 1-methyl-2-pyrrolidinone, dimethylformamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, triethylphosphate, and 2,2xe2x80x2-dipyridyl. The preferred compound of formula IV is [4R-[3(2R,3R)]]4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one, and the preferred solvate of said compound is [4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one, 1-methyl-2-pyrrolidinone solvate.
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, includes O-alkyl groups wherein xe2x80x9calkylxe2x80x9d0 is defined above.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived form an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
The term xe2x80x9cheteroarylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as pyridyl, furyl, thienyl, isoquinolyl, pyrimidinyl, and pyrazinyl.
The term xe2x80x9cenantiomerxe2x80x9d as used herein in reference to the compound of formula X 
means a compound of the formula 
The term xe2x80x9cenantiomerxe2x80x9d as used herein in reference to the compound of formula IX 
means a compound of the formula 
The term xe2x80x9cenantiomerxe2x80x9d as used herein in reference to a compound of formula VII 
means a compound of the formula 
The term xe2x80x9cenantiomerxe2x80x9d as used herein in reference to a compound of the formula VI 
means a compound of the formula 
The term xe2x80x9cenantiomerxe2x80x9d as used herein in reference to a compound of the formula V 
means a compound of the formula 
The term xe2x80x9cenantiomerxe2x80x9d as used herein in reference to a compound of the formula IV 
means a compound of the formula 
The term xe2x80x9cenantiomerxe2x80x9d as used herein in reference to a compound of the formula XVII 
means a compound of the formula 
The term xe2x80x9cenantiomerxe2x80x9d as used herein in reference to a compound of the formula XIX 
means a compound of the formula 
The process of the present invention and the preparation of the compounds of the present invention are illustrated in the following Schemes. In the following Schemes and discussion that follows, unless otherwise indicated, R1, R2, R3, R4, R5, R6, R7, R8, R11, Y, Z, X, Xc, and Xxe2x80x2 are as defined above. The following Schemes and the discussion that follows describe the preparation of the compounds of formulas I-XIX. The following Schemes and description that follows also applies to the enantiomers of the compounds of formulas I-XIX, wherein the term xe2x80x9cenantiomerxe2x80x9d is as defined above. 
Overall, the synthetic sequence in Scheme I involves attaching chiral auxiliary Xc to R1-containing compound I (step 1), asymmetric aldol condensation with aldehyde III (step 2 or 2xe2x80x2), reductive removal of the chiral auxiliary from aldol IV (step 3), base-mediated cyclization of diol V (step 4), lithiation and boration of halochromanol VI (step 5), coupling boronic acid VII with aryl halide or sulfonate VIII (step 6), and hydrolysis of ester IX (step 7).
In step 1 of Scheme 1, chiral auxiliary HXc is converted to the corresponding anion by treatment with a suitably strong base, such as an alkyllithium base, preferably butyllithium, in an aprotic solvent, such as an ethereal solvent, preferably tetrahydrofuran (THF), at a temperature of approximately xe2x88x9280 to 0xc2x0C., preferably xe2x88x9278 to xe2x88x9255xc2x0 C., over a period of about 20 minutes to one hour. Substituent Xc is a chiral auxiliary that is suitable to control relative and absolute stereochemistry in asymmetric aldol reactions. Examples of HXc include (R)-4-benzyl-2-oxazolidinone, (S)-4-benzyl-2-oxazolidinone, (4R,5S)-4-methyl-5-phenyl-oxazolidin-2-one, and (4S,5R)-4-methyl-5-phenyl-oxazolidin-2-one. The resulting anion is treated with acylating agent I, wherein group W is a halide, preferably chloride, and R1 is as defined above, in the same solvent at a temperature of approximately xe2x88x9280 to 0xc2x0 C., preferably about xe2x88x9275xc2x0 C., over a period of about one hour, and then warmed to approximately xe2x88x9220 to 20xc2x0 C., preferably about 0xc2x0 C., before aqueous workup, which is preferably done by treatment with aqueous sodium bicarbonate, to yield acylated chiral auxiliary II.
Step 2 of Scheme 1 is an xe2x80x9cEvans aldolxe2x80x9d reaction that is performed under conditions that are analogous to those described in Evans, D. A.; Bartroli, J.; Shih, T. L., J. Am. Chem. Soc. 1981, 103, 2127 and Gage, J. R.; Evans, D. A., Org. Syn. 1989, 68, 83, both of which references are incorporated herein by reference. In particular, in step 2 of Scheme 1, the acylated chiral auxiliary II is treated with a Lewis acid, a base, and substituted benzaldehyde III to yield alcohol IV with a high degree of stereoselectivity. Benzaldehyde III is substituted with ortho substituent Y which serves as a leaving group during cyclization step 4, group X (or Xxe2x80x2for Scheme 2, in particular coupling step 4 of Scheme 2) which is substituted by the aryl sidechain during coupling step 6, and substituent R2 which is as defined above. Substituent X (or Xxe2x80x2 for Scheme 2) is attached at position 4 or 5 of the phenyl moiety of benzaldehyde III. The leaving group Y is typically a halo or nitro group and X is a halide (and, for Scheme 2, Xxe2x80x2 is a halide or C1-C4 perfluoroalkylsulfonate). To prepare aldol product IV, acylated chiral auxiliary II is treated with a boron halide or sulfonate, such as a dialkylboron sulfonate, preferably dibutylboron triflate, in an aprotic solvent, such as dichloromethane, 1,2-dichloroethane, toluene, or diethyl ether, preferably dichloromethane, at a temperature of about xe2x88x9278 to 40xc2x0 C., preferably xe2x88x925xc2x0 C., over a period of about 20 minutes, followed by treatment with a tertiary amine base, such as triethylamine or diisopropylethylamine, preferably triethylamine, at a temperature of about xe2x88x9278 to 40xc2x0 C., preferably xe2x88x925 to 5xc2x0 C., over a period of about one hour. This mixture is treated with substituted benzaldehyde III at a temperature of about xe2x88x92100 to 0xc2x0 C., preferably about xe2x88x9270xc2x0 C., over a period of about 30 minutes. This mixture is allowed to warm to a temperature of about xe2x88x9220 to 25xc2x0 C., preferably about xe2x88x9210xc2x0 C., over a period of about one hour, and then treated with a protic oxidative quench, preferably by the successive addition of a pH 7 buffer solution, methanol, and aqueous hydrogen peroxide, at a temperature of less than about 15xc2x0 C., to yield alcohol IV.
Step 2xe2x80x2 of Scheme 1 is an alternative, and preferable, method of providing alcohol IV using a titanium-containing Lewis acid. In step 2xe2x80x2 of Scheme 1, acylated chiral auxiliary II is treated with a titanium(IV) halide, preferably titanium tetrachloride, in an aprotic solvent such as dichloromethane, 1,2-dichloroethane, or toluene, preferably dichloromethane, at a temperature of about xe2x88x9280 to 0xc2x0 C., preferably xe2x88x9280 to xe2x88x9270xc2x0 C., over a period of about 30 minutes with additional stirring for about 30 minutes, followed by treatment with a tertiary amine or tertiary diamine base, such as triethylamine or N,N,Nxe2x80x2Nxe2x80x2-tetramethylethylenediamine, preferably N,N,Nxe2x80x2Nxe2x80x2-tetramethylethylenediamine, at a temperature of about xe2x88x9280 to 0xc2x0 C., preferably xe2x88x9280 to xe2x88x9265xc2x0 C., over a period of about 30 minutes. This is optionally, and preferably, followed by treatment with a donor ligand, such as 1-methyl-2-pyrrolidinone, dimethylformamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone,triethylphosphate, or 2,2xe2x80x2-dipyridyl, preferably 1-methyl-2-pyrrolidinone, at a temperature of about xe2x88x9280 to 0xc2x0 C., preferably xe2x88x9280 to xe2x88x9265xc2x0 C., followed by stirring for a period of about 30 minutes. This mixture is treated with substituted benzaldehyde III at a temperature of about xe2x88x92100 to 0xc2x0 C., preferably xe2x88x9280 to xe2x88x9265xc2x0 C., over a period of about 30 minutes, and allowed to warm to a temperature of xe2x88x9230 to 30xc2x0 C., preferably 0 to 25xc2x0 C., over a period of about one to 24 hours, preferably about 4 hours. This mixture is treated with a protic quench, preferably aqueous ammonium chloride, at a temperature of xe2x88x9230 to 30xc2x0 C., preferably 0 to 25xc2x0 C., to yield alcohol IV. Where treatment with a donor ligand is done, the alcohol IV is, in some cases, provided as a crystalline solvate with the donor ligand. Stirring the quenched reaction mixture with a solid support such as Celite(copyright)for a period of about 12 hours at a temperature of about 20xc2x0 C. improves the filtration of the reaction mixture for removal of titanium byproducts.
The titanium aldol conditions of step 2xe2x80x2 of Scheme 1 are preferable and operationally more simple than the boron aldol conditions of step 2 of Scheme 1 in that they avoid the pyrophoric reagent tributylborane, the corrosive reagent triflic acid, and their exothermic combination in the preparation of the Lewis acid dibutylboron triflate. Further, in contrast to titanium aldol reactions described in the literature, such as in Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F., J. Am. Chem. Soc. 1991, 113, 1047, the titanium aldol conditions of step 2xe2x80x2 of Scheme 1 provide high selectivity with less than two equivalents of the aldehyde III. Preferably, about one equivalent of aldehyde III is used in this step. The phrase xe2x80x9cabout one equivalentxe2x80x9d as used herein in reference to aldehyde III or a compound of the formula R11C(O)H (as recited in the claims) means less than 1.5 equivalents of said compound. In the foregoing article by Evans et al., it is reported that two equivalents of aldehyde would be required for a titanium aldol reaction analogous to step 2xe2x80x2 of Scheme 1.
In addition to having utility in the preparation of the therapeutic agents of formula X, the titanium aldol conditions of step 2xe2x80x2 of Scheme 1 are useful in the preparation of HIV protease inhibitor compounds that are described in United Kingdom patent application number 2,270,914 (published Mar. 30, 1994) and in B. D. Dorsey et al. Tetrahedron Letters, 1993, 34(12), 1851. Scheme 4 illustrates the application of titanium aldol reaction to aldehyde XVIII in which R11 is C1-C9 alkyl, C2-C9 alkenyl, or phenyl substituted by Y in the 2 position, X in the 4 or 5 position, and R2 in one of the remaining positions of the phenyl moiety, wherein Y, X and R2 are as defined above. The reaction conditions for Scheme 4 are the same as those described above for step 2xe2x80x2 of Scheme 1. Aldehyde XVIII encompasses aldehyde III from Scheme 1, and alcohol XIX encompasses alcohol IV from Scheme 1. The reaction of Scheme 4 can be used prepare the HIV protease inhibitor compounds that are described in United Kingdom patent application number 2,270,914, referred to above, where R11 is C1-C9 alkyl or C2-C9 alkenyl, preferably 3-cyclohexylpropenyl.
Table 1 below illustrates how the product of Scheme 4 or step 2xe2x80x2 of Scheme 1 an vary depending on the reaction conditions that are used, and, in particular, how the diastereoselectivity increases by increasing the amount TMEDA from 1.2 to 3 equivalents and by the addition of 2 equivalents of NMP. In Table 1, 1.0 equivalent of aldehyde RCHO was used for each reaction, x and y represent equivalents of base and NMP, respectively, NMP means 1-methyl-2-pyrrolidinone, TMEDA means N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine, NEtiPr2 means diisopropylethylamine, and the ratio of diastereomers was determined by HPLC. The aldol isomers were identified by separation and conversion to known carboxylic acid isomers by hydrolysis with LiOH/H2O2 according to procedures analogous to those described in Van Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.; Heathcock, C. H., J. Org. Chem. 1991, 56, 2499 and Gage, J. R.; Evans, D. A., Org. Syn. 1989, 68, 83. The desired isomer is indicated in bold. 
In step 3 of Scheme 1, chiral auxiliary Xc is removed (and optionally recovered for reuse in step 1), and the oxidation state of compound IV (acid level) is reduced to the desired alcohol V according to a procedure analogous to the procedure described in Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.; Miyashiro, J. M.; Rowell, B. W.; Yu, S. S., Syn. Commun. 1990, 20, 307, which is incorporated herein by reference. In this process, alcohol IV is treated with a hydride reducing agent, such as lithium borohydride, lithium aluminum hydride, sodium borohydride, or calcium borohydride, preferably lithium borohydride, in an ethereal solvent such as THF, diisopropyl ether, or methyl tert-butyl ether, preferably THF, typically containing a protic solvent, such as water, ethanol, or isopropanol, at a temperature of about xe2x88x9278xc2x0 C. to reflux temperature, preferably 0xc2x0 C. to ambient temperature (20-25xc2x0 C.). After a period of one to 24 hours, typically 12 hours, the reaction is quenched with water with the optional subsequent addition of hydrogen peroxide. Chiral auxiliary HXc can be recovered for reuse in step 1 by selective precipitation, or by extraction of HXc into aqueous acid, preferably hydrochloric acid, from a solution of diol V in an organic solvent such as diisopropyl ethyl or a mixture of ethyl acetate and hexane, followed by neutralization of the aqueous acidic extracts with base, and extraction of HXc into an organic solvent.
Step 4 of Scheme 1 is an intramolecular aromatic substitution whereby the primary hydroxyl in diol V displaces ortho leaving group Y to generate the chromanol ring system of VI. In particular, diol V, in which leaving group Y is a halo or nitro group, preferably a fluoro group, is treated with a base, such as potassium tert-butoxide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, cesium carbonate, or sodium hydride, preferably potassium tert-butoxide, in an aprotic solvent such as THF, dimethyl sulfoxide, or 1-methyl-2-pyrrolidinone, preferably THF, optionally in the presence of added copper salts, at a temperature of between ambient temperature and 130xc2x0 C., preferably about 70xc2x0 C., for a period of one to 24 hours, typically about four hours, giving chromanol VI. In chromanol VI, the substituent X (or Xxe2x80x2 for Scheme 2) is attached at position 6 or 7 of the chroman ring.
In step 5 of Scheme 1, substituent X in chromanol VI is converted to lithium and then a boronic acid group. For lithiation, chromanol VI is preferably treated first with methyl lithium to form the lithium alkoxide followed by butyl lithium to form the aryl lithium. In this process, chromanol VI, in which X is a halide, preferably bromide or iodide, is treated with two equivalents of alkyllithium, preferably first with one equivalent of methyllithium followed by one equivalent of butyl lithium, in an ethereal solvent, preferably THF, at a temperature of xe2x88x9278 to 0xc2x0 C., preferably xe2x88x9270 to xe2x88x9265xc2x0 C., for a period of about one hour, followed by treatment with a borating agent, such as borane-tetrahydrofuran complex, triisopropyl borate, or trimethyl borate, preferably borane-THF complex, at a temperature of xe2x88x9278 to 0xc2x0 C., preferably xe2x88x9270 to xe2x88x9265xc2x0 C., over a period of about 30 minutes, followed by quenching with water or optionally aqueous acid at a temperature of about xe2x88x9265xc2x0 C. to ambient temperature, preferably at about 0xc2x0 C., giving boronic acid VII in which the boronic acid moiety is attached at position 6 or 7 of the chroman ring.
Step 6 of Scheme 1 is a Suzuki coupling between boronic acid VII and compound VIII to form the biaryl bond of compound IX. In compound VIII, Z is a halide or sulfonate, preferably bromide, iodide, or trifluoromethanesulfonate, R4 is C1-C6 alkyl and R3 is as defined above. This procedure is analogous to the procedure described in Miyaura, N.; Suzuki, A., Chem. Rev. 1995, 95, 2457, which is incorporated herein by reference. This procedure is preferable to the coupling of zinc or tin species due to the difficulty of preparing organozincs on a large scale and the toxicity of organotin compounds. In this process, a mixture of boronic acid VII, arene VIII, a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate, allylpalladium chloride dimer, tris(dibenzylideneacetone)dipalladium(0), or 10% palladium on carbon, preferably 10% palladium on carbon, and a base or fluoride salt, such as sodium carbonate, triethylamine, sodium bicarbonate, cesium carbonate, tripotassium phosphate, potassium fluoride, cesium fluoride, or tetrabutylammonium fluoride, preferably potassium fluoride, in a solvent such as ethanol, dimethoxyethane, or toluene, optionally containing water, preferably ethanol, are stirred at a temperature of between ambient temperature and 130xc2x0 C., preferably reflux temperature, for a period of about one to about 24 hours, preferably about three hours, giving biaryl IX in which the benzyl ester moiety is attached at position 6 or 7 of the chroman ring.
In step 7 of Scheme 1, ester IX is treated with aqueous hydroxide base, such as aqueous sodium hydroxide, in an alcoholic solvent, such as isopropyl alcohol, at a temperature of between 40xc2x0 C. and reflux temperature, preferably reflux temperature, for a period of about one to about 24 hours, preferably about six hours. The reaction mixture is cooled to ambient temperature and partitioned between aqueous base and an organic solvent, such as a mixture of hexane and isopropyl ether. The aqueous solution is acidified, and the final compound X is extracted into an organic solvent such as ethyl acetate. This method of extracting the compound X with organic solvents removes neutral impurities which is particularly advantageous in the last step of this synthesis.
To facilitate the handling of carboxylic acid X, this compound can be treated with a secondary amine of the formula NHR5R6, wherein R5 and R6 are as defined above, in a solvent such as toluene, to form an ammonium carboxylate of the formula 
wherein R1, R2, R3, R5 and R6 are as defined above. Ammonium carboxylate XVII can be treated with an aqueous acid such a hydrochloric acid or sulphuric acid, preferably hydrochloric acid, in a solvent such as ethyl acetate, toluene, or methylene chloride, preferably ethyl acetate, at a temperature ranging from 0xc2x0 C. to ambient temperature for a period of 30 minutes to 3 hours, preferably 1 hour, to provide carboxylic acid X.
Scheme 2 illustrates an alternative to the coupling sequence of steps 5 and 6 of Scheme 1. The process of Scheme 2 is preferred. Step 1 of Scheme 2 is an esterification of carboxylic acid XI with alcohol R4OH, in which R3 and R4 are as defined above, to generate ester XII. In this process, carboxylic acid XI is treated with alcohol R4OH, preferably a primary or secondary alcohol such as 2,2-dimethyl-propyl alcohol, and an acid such as sulfuric acid, hydrochloric acid, methanesulfonic acid, toluenesulfonic acid, or camphor sulfonic acid, preferably sulfuric acid, in a solvent such as toluene, dichloromethane, or dichloroethane, preferably toluene, at a temperature of 0xc2x0 C. to reflux temperature, preferably reflux temperature, for a period of one to 24 hours, typically 4 hours, to provide ester XII.
In step 2 of Scheme 2, ester XII is treated with a base and the resulting ortho metallated species is trapped with a trialkylborate to give boronate ester XIII. In step 3 of Scheme 2, the boronate ester XIII is hydrolyzed to the corresponding boronic acid XIV which is performed by methods known to those skilled in the art. In steps 2 and 3 of Scheme 2, ester XII is treated with a metal amide base such as lithium diisopropylamide, lithium diethylamide, lithium 2,2,6,6-tetramethylpiperidine, or bis(2,2,6,6-tetramethylpiperidino)magnesium, preferably lithium diisopropylamide, in the presence of a tri-(C1-C4 alkyl)borate, such as triisopropylborate, triethylborate, or trimethylborate, preferably triisopropylborate, in an ethereal solvent, such as THF, diisopropyl ether, dioxane, or methyl tert-butyl ether, preferably THF, over a temperature range of about xe2x88x9278xc2x0 C. to ambient temperature (20-25xc2x0 C.), preferably about 0xc2x0 C. After a period of 10 minutes to 5 hours, typically 1 hour, the reaction is quenched with aqueous acid to provide boronic acid XIV.
To facilite the handling of boronic acid XIV before proceeding to step 4 of Scheme 2, the boronic acid XIV can be reacted with an aminodiol as illustrated in Scheme 3. In Scheme 3, boronic acid XIV is reacted with aminodiol XV, wherein R8, m and n are as defined above, in a solvent such as isopropanol, ethanol, methanol, hexanes, toluene, or a combination of the foregoing solvents, preferably isopropanol, at a temperature within the range of 0xc2x0 C. to reflux temperature, preferably ambient temperature, for a period of 15 minutes to 10 hours, preferably 10 hours, to provide the amine complex XVI. To proceed with step 4 of Scheme 2, amine complex XV is hydrolyzed to boronic acid XIV according to methods known to those skilled in the art. Such methods include the use of aqueous acid, such as hydrochloric acid.
Step 4 of Scheme 2 is a Suzuki coupling between boronic acid XIV and chromanol VI to form the biaryl bound of IX. In this process, a mixture is prepared containing boronic acid XIV, chromanol VI, a palladium catalyst, such as tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate, allylpalladium chloride dimer, tris(dibenzylideneacetone)dipalladium(0), or 10% palladium on carbon, preferably tetrakis(triphenylphosphine)palladium(0), a base or fluoride salt, such as sodium carbonate, triethylamine, sodium bicarbonate, cesium carbonate, tripotassium phosphate, pottasium fluoride, cesium fluoride, sodium hydroxide, barium hydroxide, or tetrabutylammonium fluoride, preferably sodium carbonate, and a solvent such as toluene, ethanol, dimethoxyethane, optionally containing water, preferably toluene containing water. In chromanol VI, which is prepared according to Scheme 1, Xxe2x80x2, which is attached at position 6 or 7 of the chroman ring, represents a halide or C1-C4 perfluoroalkylsulfonate, preferably bromide, iodide, or trifluoromethanesulfonate. The mixture is stirred at a temperature of between ambient temperature and reflux temperature, preferably reflux temperature, for a period of about 10 minutes to about 6 hours, preferably 1 hour, to provide biaryl IX.
In step 5 of Scheme 2, ester IX is hydrolyzed to provide the carboxylic acid X as described above for step 7 of Scheme 1.
The present invention is illustrated by the following examples, but it is not limited to the details thereof. In the following examples, the term xe2x80x9cambient temperaturexe2x80x9d means a temperature within the range of about 20xc2x0 C. to about 25xc2x0 C.